Inflammation in the tumor microenvironment is now recognized as a strong promoter of tumor growth. Substantial epidemiological evidence suggests that aspirin, which suppresses inflammation, also reduces the risk of cancer. However, the mechanism by which aspirin inhibits cancer remains unclear and toxicity has limited its clinical use. Aspirin not only blocks prostaglandin synthesis but, as more recently discovered, also stimulates the production of anti-inflammatory mediators, such as aspirin-triggered resolvins (AT-RvDs). Resolvins are novel pro-resolution lipid mediators derived from omega-3 polyunsaturated fatty acids and are being evaluated as effective anti-inflammatory agents in phase III ocular human clinical trials. We recently discovered that resolvins have potent anti-tumor activity making resolvins important candidates to mediate the anti-cancer activity of aspirin. Thus, we hypothesize that aspirin's tumor-inhibitory effect is mediated in part by aspirin triggered resolvins via novel anti-inflammatory and pro-resolution mechanisms rather than due to blocking prostaglandins alone. The overall goal of this project is to determine whether the anti-cancer activity of resolvins can be harnessed to eradicate cancer by an entirely novel approach which manipulates endogenous pro-resolving mediators. In Aim 1 we will establish in animal models that AT-RvDs have broad anti-cancer activity and elucidate the cellular mechanisms of action that regulate the inflammation-clearing effect of resolvins. This will set the foundation for Aim 2 which is to determine whether aspirin's anti-cancer activity is mediated by AT-RvD1. To abrogate resolvin receptor activity we will use genetically engineered mice that lack the RvD1 receptor ALX/FPR-2 and a pharmacological antagonist of its receptor (ALX/FPR-2). Manipulating the resolvin pathway will also be achieved with transgenic (fat-1) mice which have increased endogenous omega-3 fatty acids (the substrates of AT-RvDs). These studies lay the groundwork to optimize the resolvin pathway to inhibit or prevent cancer in preclinical studies for translation to humans. Thus in Aim 3 we will compare the toxicity profiles of resolvins to aspirin (i.e. in gastric bleeding and aspirin-induced mucosal injury). To determine if resolvins can replace aspirin in chemoprevention experiments, we will recapitulate the human experience with aspirin using the murine model of ApcMin/+ colon carcinogenesis. This pre-clinical characterization will establish a new direction in cancer research and guide us in determining the optimal way to use resolvins in cancer trials in humans. Understanding the role of resolvins in cancer is of direct clinical relevance for two reasons: (1) resolvins may provide a novel pathway and molecular mechanism to explain how aspirin reduces cancer risk so broadly; (2) since resolvins are active at over 10,000-fold lower concentration than aspirin and are naturally produced by the human body, these anti-inflammatory lipid mediators hold great promise to be the safest choice for treatment of chronic inflammatory diseases, including cancer.